Obesity is a medical condition in which body fat has accumulated overly due to the imbalance between the intake and consumption of energy. Obesity is attributable to many causes, including genetic factors, environmental factors such as westernized diet, psychological factors such as stress, and so forth. But, the exact cause or its mechanism has not been clearly elucidated. In addition to its own risk, obesity increases the likelihood of hyperinsulinemia, arteriosclerosis and cardiovascular diseases. Therefore, many studies are underway globally for the treatment of obesity (Nature, 404: 635643, 2000; JAMA, 282: 15231529, 1999).
Representative obesity-treating drugs include Reductil™ (Abbott, USA), Xenical™ (Roche, Switzerland) and Exolise™ (Arkopharma, France). However, because of side effects associated with cardiac, respiratory and neurologic disorders as well as short-lasting effect, development of more effective obesity-treating drugs is necessary. The current strategy for development of anti-obesity drugs is focused on reducing appetite, lowering caloric absorption, increasing thermogenesis, regulating energy metabolism, regulating signal transduction via the nervous system, and the like (Nature, 404: 635643, 2000). Despite the continued efforts to treat obesity based on these strategies, it is not easy to develop a drug satisfying both the safety and efficiency requirements. In this regard, to find and use the ingredients conforming to the obesity-treating strategy from natural products with well-proven safety will be more efficient than to develop synthetic drugs.
Sterol regulatory element-binding proteins (SREBPs) are important transcription factors that activate the enzymes involved in the biosynthesis of fatty acid and cholesterol and thus regulate the synthesis of cholesterol and fatty acid in the liver and adipocytes. Hyperinsulinemia caused by insulin resistance increases expression of SREBP1 in the liver, resulting in accumulation of triglyceride in the liver and fat tissue (Horton, J. D., et al., Proc Natl Acad Sci USA, 95, 5987-5992, 1998). Thus, it is regarded that SREBP1 plays a key role in fatty liver induced by insulin resistance.
5′ AMP-activated protein kinase (AMPK) is an enzyme that is mainly expressed in tissues related with energy metabolism, such as the liver, muscles and fats, and plays an important role in cellular energy metabolism. AMPK becomes activated when cellular energy level is decreased due to exercise, hypoxia, ischemia, etc. and thus regulates metabolism-related enzymes. That is to say, by regulating fatty acid and cholesterol synthesis, fatty acid oxidation and glycolysis, it restores the intracellular energy balance. Accordingly, it has attracted a lot of attention as a target gene for development of treatments for various metabolic diseases including diabetes, obesity, or the like.
AMPK inhibits fatty acid synthesis by phosphorylating and inactivating the fatty acid synthase, acetyl-CoA carboxylase (ACC), and stimulates fatty acid oxidation by increasing the activity of carnitine parmitoyltransferase 1 which transports fatty acids into the mitochondria (Winder W W, Hardie D G. Am J Physiol 270: E299-304, 1996).
Also, AMPK inhibits cholesterol synthesis by inhibiting the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), a key enzyme in cholesterol biosynthesis (Henin, N., M. F. Vincent, H. E. Gruber, and G. Van den Berghe. FASEB J. 9: 541-546, 1995).
AMPK is known to facilitate cellular glucose uptake by translocating glucose transporter 4 (GLUT4) to the plasma membrane independently of the insulin signaling. Indeed, the antidiabetic drug metformin reduces blood sugar level by activating AMPK (Kurth-Kraczek E J, Hirshman M F, Goodyear L J, Winder W W. Diabetes 48 (8): 166771, 1999; Winder W W. Hardie D G. Am J Physiol 270: E299-304, 1996).